Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever. DENV and its mosquito vectors are widely distributed in tropical and subtropical regions and the disease is endemic in over 100 countries. There are no approved vaccines for dengue.
Dengue virus induced antibody responses are mainly targeted against the envelope (E) protein. Many non-neutralizing antibodies are cross-reactive between the 4 different DENV serotypes (DENV-1-4) and recognize specific epitopes on E that do not attribute to the protection against DENV infections. Highly potent neutralizing antibodies are often targeted against epitopes that require higher order quaternary protein structures that are assembled and displayed on intact virions only. Between serotypes, the neutralizing epitopes differ in structure, complexity and location. These serotype specific neutralizing antibodies render protection against subsequent virus infections of the same serotype.
Leading dengue vaccines are based on tetravalent attenuated live dengue virus formulations. A recent human efficacy study with a live vaccine failed to generate balanced protective immune responses to all 4 serotypes. Moreover, some vaccinated people appear to have higher risk of developing disease after natural infections. Vaccines based on recombinant dengue E proteins are likely to be safer and easier to balance across the 4 serotypes. However, as recombinant proteins are secreted as monomers, the key quaternary epitopes targeted by human antibodies are not displayed on recombinant proteins.
The present invention overcomes previous shortcomings in the art by providing compositions and methods directed to reconstructing complex quaternary neutralizing epitopes on artificial surfaces for use in diagnostics and vaccines.